Abstract
In multiple sclerosis (MS), a non-random and clinically relevant pattern of gray matter (GM) volume loss has been described. Whether differences in regional gene expression might underlay distinctive pathological processes contributing to this regional variability has not been explored yet. Two hundred eighty-six MS patients and 172 healthy controls (HC) underwent a brain 3T MRI, a complete neurological evaluation and a neuropsychological assessment. Using Allen Human Brain Atlas, voxel-based morphometry and MENGA platform, we integrated brain transcriptome and neuroimaging data to explore the spatial cross-correlations between regional GM volume loss and expressions of 2710 genes involved in MS (p < 0.05, family-wise error-corrected). Enrichment analyses were performed to evaluate overrepresented molecular functions, biological processes and cellular components involving genes significantly associated with voxel-based morphometry-derived GM maps (p < 0.05, Bonferroni-corrected). A diffuse GM volume loss was found in MS patients compared to HC and it was spatially correlated with 74 genes involved in GABA neurotransmission and mitochondrial oxidoreductase activity mainly expressed in neurons and astrocytes. A more severe GM volume loss was spatially associated, in more disabled MS patients, with 44 genes involved in mitochondrial integrity of all resident cells of the central nervous system (CNS) and, in cognitively impaired MS patients, with 64 genes involved in mitochondrial protein heterodimerization and oxidoreductase activities expressed also in microglia and endothelial cells. Specific differences in the expressions of genes involved in synaptic GABA receptor activities and mitochondrial functions in resident CNS cells may influence regional susceptibility to MS-related excitatory/inhibitory imbalance and oxidative stress, and subsequently, to GM volume loss.
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Data availability
The anonymized dataset used and analyzed during the current study is available from the corresponding author upon reasonable request.
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P. Preziosa contributed to the conception of the study, acquisition, analysis and interpretation of clinical and MRI data, drafting and revising the text and preparing the figures. L.Storelli contributed to the acquisition, analysis and interpretation of MRI data and revising the manuscript. N. Tedone, M. Margoni, D. Mistri, M. Azzimonti contributed to the acquisition, analysis and interpretation of MRI data and revising the manuscript. M.A. Rocca and M. Filippi contributed to the conception of the study, drafting and revising the text, acting as the study supervisors. All the authors gave their approval to the current version of the manuscript.
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The authors declare that they have no competing interests in relation to this work. Potential conflicts of interest outside the submitted work are as follows: P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. L. Storelli declared the receipt of grants and contracts from FISM-Fondazione Italiana Sclerosi Multipla-within a fellowship program (cod. 2019/BR/009). N. Tedone, D. Mistri and M. Azzimonti report no competing interests. M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders.
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Preziosa, P., Storelli, L., Tedone, N. et al. Spatial correspondence among regional gene expressions and gray matter volume loss in multiple sclerosis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02452-5
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DOI: https://doi.org/10.1038/s41380-024-02452-5